Eicosanoids are an important class of lipid mediators which modulate a wide variety of physiological functions and play a central role in a number of inflammatory diseases such as asthma, arthritis, and psoriasis. In many cell types the rate-determining step in the generation of eicosanoids is the release of arachidonic acid (AA) from its cellular store in the phospholipid pool. A number of different pathways for the mobilization of AA have been proposed, but many detailed studies of the distribution and stoichiometry of metabolites have demonstrated the importance of phospholipase A.sub.2 (PLA.sub.2) as a major mediator of agonist-induced AA release [Imai, A., Yano, K., Kameyama, Y., and Nozawa, Y. (1992) Japan J. Exp. Med. 52, 99-105; Maede, C. J., Turner, G. A., and Bateman, P. E. (1986) Biochem. J. 238, 425-436; Chau, L. -Y. and Tai, H. -H. (1983) Biochem. Biophys. Res. Commun. 113, 241-247]. Over the past decade a number of distinct types of PLA.sub.2 have been isolated and characterized. The best known of these are; a family of 14-kDa calcium-dependent secreted enzymes, and an 85-kDa cytosolic calcium-dependent enzyme (cPLA.sub.2). The 14-kDa enzymes are secreted from the cell into the extracellular environment where they participate in the digestion of biological materials. The cPLA.sub.2 is found in low abundance in the cell, and is thought to be involved in the release of AA for eicosanoid production since it preferentially hydrolyzes phospholipids containing AA at the sn-2 position [Clark, J. D., Lin, L. L., Kriz, R. W., Ramesha, C. S., Sultzman, L. A., Lin, A. Y., Milona, N., and Knopf, J. L. (1991) Cell 65, 1043-1051; Hanel, A. M., Shcuttel, S., and Gelb, M. H. (1993) Biochemistry 32, 5949-59581, responds to physiological changes in calcium concentration by translocating to membranes [Clark, J. D., Lin, L. L., Kriz, R. W., Ramesha, C. S., Sultzman, L. A., Lin, A. Y., Milona, N., and Knopf, J. L. (1991) Cell 65, 1043-1051; Kramer, R. M., Roberts, E. F., Manetta, J. V., Sportsman, J. R., and Jakubowski, J. A. (1993) J. Lip. Mediators 6, 209-216], and is activated by hormonal signaling through phosphorylation of a serine residue [Lin, L. L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A., and Davis, R. J. (1993) Cell 72, 269-278; Lin. L. L., Lin, A. Y., and Knopf, J. L. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 6147-6151].
Since it is proposed that the cPLA.sub.2 plays a major role in the mobilization of AA for eicosanoid biosynthesis selective inhibitors of this enzyme may be of use in controlling a wide variety of inflammatory diseases.